Cisatracurium besylate is the common name of the compound (1R,1′R,2R,2′R)-2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl]-isoquinolinium dibenzenesulfonate, and it is represented by the structural formula (I):

Cisatracurium besylate is the 1R-cis,1′R-cis isomer of atracurium besylate, otherwise known as 2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl]-isoquinolinium dibenzenesulfonate. Atracurium besylate has four chiral centers, which should theoretically allow for 16 possible isomers. Due to the symmetry of the molecule the number of possible isomers is reduced to 10. Cisatracurium besylate is one of 10 isomers of atracurium besylate. See, e.g., J. B. Stenlake et al. in “Biodegradable neuromuscular blocking agents,” Eur. J. Med. Chem.-Chem. Ther., vol. 19, issue 5, pp. 441-450 (1984).
Cisatracurium besylate is a nondepolarizing neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU).
Cisatracurium besylate is marketed in the United States, Europe and other countries by GlaxoSmithKline and Abbott Laboratories under the trade name Nimbex®. Nimbex® is a sterile, non-pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzenesulfonic acid. The drug is provided in 2.5 ml, 5 ml and 10 ml vials having strength of 2 mg/ml cisatracurium besylate. A 30 ml vial containing 5 mg/ml cisatracurium besylate is also available.
The potency of the cisatracurium besylate in the formulated, Nimbex® decreases with time at a rate of approximately 5% per year under refrigeration (5° C.). Nimbex should be refrigerated at 2° to 8° C. (36° to 46° F.) to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C. (77° F.).
U.S. Pat. No. 4,179,507 (“the '507 patent”) describes the preparation of a series of bis-veratrylisoquinolinium quaternary ammonium salts, including atracurium besylate. The '507 patent describes the preparation of atracurium besylate by a process that involves coupling (±)-tetrahydropapaverine base (compound II) with 1,5-pentamethylene diacrylate (compound III) and treating the resulting tertiary amine base with oxalic acid to produce N,N′-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropapaverine dioxalate (compound IV). This salt is converted to the free base (compound V), which is treated with methyl benzenesulfonate. The resulting product, atracurium besylate (compound VI), is precipitated and isolated. The process is illustrated below in Scheme 1.

European application No. 0219616 (“the '616 application”) discloses the synthesis of atracurium chloride. The '616 application describes a process that involves coupling of 1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinepropanoic acid (compound VII) with 1,5-pentanediol in the presence of an acid to afford the diester (compound IX). The resulting diester is quaternized with methyl iodide to form atracurium iodide, which is then converted into atracurium chloride by means of anion exchange. The process is illustrated below in Scheme 2.
The above-mentioned references do not disclose isomer resolution or how to isolate and purify a single isomer.
U.S. Pat. Nos. 5,453,510 and 5,556,978 (“the '510 patent” and “the '978 patent”) disclose cisatracurium besylate. According to these documents, cisatracurium besylate is obtained by a process involving the formation of (R)-tetrahydropapaverine by resolving the racemic mixture of compound (II) with the chiral amino acid N-acetyl-L-leucine and crystallizing from acetone to afford (R)-tetrahydropapaverine-N-acetyl-L-leucinate in 97% yield, which is converted into (R)-tetrahydropapaverine base. The (R)-tetrahydropapaverine obtained is than reacted with 1,5-pentamethylene diacrylate followed by oxalic acid to afford the dioxalate salt of (1R,1′R)-2,2′-(3,11-dioxo-4,10-dioxamidecamethylene)-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-veratrylisoquinoline). Conversion of the dioxalate salt into the free base, followed by treatment with methyl benzenesulfonate, affords a solution of (1R,1′R)-atracurium besylate. After lyophilization a pale yellow solid is obtained containing a mixture of the three isomers: 1R-cis,1′R-cis; 1R-cis,1′R-trans; 1R-trans,1′R-trans (hereinafter referred to as the “R-atracurium besylate mixture”) in a ratio of about 58:34:6 respectively. The R-atracurium besylate mixture is subjected to preparative HPLC column chromatography on silica using a mixture of dichloromethane, methanol and benzenesulfonic acid in the ratio of 4000:500:0.25 as the eluent. The fractions containing the required isomer are collected and further processed to afford cisatracurium besylate having an isomeric purity of about 99%.
The above procedure suffers from several disadvantages which render the processes unsuitable for commercial scaling up implementation. One major problem is attributable to the need for HPLC purification, which is undesirable in a large-scale operation because only relatively small amounts of the product can be purified at a time. The method also is expensive, time-consuming and generates large quantities of waste solvents, which raises considerations with regard to the safe disposal of accumulated wastes. Another disadvantage of the above procedures is that cisatracurium besylate may be unstable in the eluent mixture used in the HPLC separation procedure and, thus, can lead to the formation of decomposition products.
Accordingly, there is a need for an improved process for the production of cisatracurium, e.g., cisatracurium besylate, and intermediates therefor, which avoid column chromatography and can be scaled up to facilitate the large scale production of cisatracurium. The present invention provides such a process and intermediates, which can be used for producing highly pure cisatracurium besylate.